Fabrizio MusacchioA great start to #BonnBrain26 🧠 today, highlighted by the excellent young investigator talks by Martin Pofah, Samuel Eckmann, Nicole Hoffmann, Carlo Castoldi, Karen Yu Chen Cheng, Carina Seidl, Jens-Bastian Eppler and Julia Schnermann 💫💪
Forschungszentrum DZNENew paper out: Large-scale mapping of the MCH network in ALS mice reveals the vulnerability of dopaminergic and GABAergic neurons in zona incerta: Scekic-Zahirovic, Jelena; Antonucci, Stefano; Wiesner, Diana; et al.
Acta Neuropathologica Communications Vol. 14, no. 1, p. 46 http://dlvr.it/TRRf90 | Please share #dzne #papers
Acta Neuropathologica Communications Vol. 14, no. 1, p. 46 http://dlvr.it/TRRf90 | Please share #dzne #papers
Large-scale mapping of the MCH network in ALS mice reveals the vulnerability of dopaminergic and GABAergic neurons in zona incerta - DZNEPUB
Weight loss and hypermetabolism are early and prognostically significant features of amyotrophic lateral sclerosis (ALS) and are associated with hypothalamic atrophy and degeneration of melanin-concentrating hormone (MCH) neurons that regulate energy balance. To investigate whether MCH vulnerability arises from upstream network dysfunction, we performed whole-brain retrograde rabies tracing in SOD1G93A mice. We identified an early, selective loss of monosynaptic inputs from the zona incerta (ZI), a dopaminergic (DA)/gamma-aminobutyric acid (GABA)ergic nucleus that preceded MCH neuron degeneration. Neurochemical profiling confirmed the DA/GABAergic identity of these ZI input neurons, and ZI/DAergic neurons later degenerated. ALS-related pathology emerged early in the ZI, paralleling pathology in the motor cortex, while anterograde mapping revealed that motor cortical projections preferentially targeted the ZI, linking vulnerable motor and metabolic networks. Loss of ZI/DAergic neurons was observed in conjunction with weight loss in non-SOD1 ALS models. These findings identify the ZI as an early-affected node within hypothalamic networks and suggest that disruption of DA/GABAergic inputs to MCH neurons is associated with subsequent MCH and DA neuronal vulnerability, degeneration and metabolic imbalance in ALS.The online version contains supplementary material available at 10.1186/s40478-026-02231-z. Scekic-Zahirovic, Jelena; Antonucci, Stefano; Wiesner, Diana; Ebner, Chiara; El Hajj, Hussein; Aousji, Oumayma; Halablab, Kareen; Fan, Yiting; Zelaya, Anneka; Yartas, Gizem; Baskar, Karthik; Çakmak, E. Anastasia; Bayer, David; Sung, Hoon-Ki; Dupuis, Luc; Park, Jeehye; Roselli, Francesco
New paper out: Exploring neural correlates of automated speech-based cognitive markers through resting-state functional connectivity in aging and at-risk Alzheimer's disease.: Li, Qingyue; Alexopoulou, Zampeta-Sofia; Dyrba, Martin; et al.
Alzheimer's research & therapy Vol. 18, no. 1, p. 52 http://dlvr.it/TRR4zc | Please share #dzne #papers
Alzheimer's research & therapy Vol. 18, no. 1, p. 52 http://dlvr.it/TRR4zc | Please share #dzne #papers
Exploring neural correlates of automated speech-based cognitive markers through resting-state functional connectivity in aging and at-risk Alzheimer's disease. - DZNEPUB
Digital speech-based assessments provide scalable tools for detecting subtle cognitive decline. Here, we investigated whether digitally derived speech-based composite score of cognition and individual speech features were associated with alterations in functional connectivity (FC) within task-related brain networks in the Alzheimer's disease spectrum, which are known to reflect cognitive performance and disease-related changes.Data were analyzed from 129 participants of the German PROSPECT-AD study, ranging from cognitively healthy individuals to those with mild cognitive impairment. Speech-based cognitive scores and speech features were derived from automated phone-administered semantic verbal fluency (SVF) and verbal learning tasks (VLT). Resting-state fMRI assessed FC, with intrinsic connectivity networks identified via independent component analysis and dual regression. Associations were examined using permutation-based voxel-wise regression, controlling for demographic and clinical covariates. Seed-to-voxel analyses were conducted to support network identification and complement findings.Greater language network connectivity in the left middle temporal gyrus was associated with increased SVF temporal cluster switching (FWE < .05, cluster size = 12 voxels, mean T = 3.86). Exploratory analyses (uncorrected p < .01) demonstrated no significant associations between cognitive composite scores and FC. However, individual SVF and VLT speech features exhibited network-specific associations across executive, language, and default mode networks, indicating exploratory yet spatially distinct connectivity patterns.Digital speech-based assessments may have limited current utility for detecting FC alterations in at-risk individuals. Further validation using complementary methodological approaches, shorter intervals between fMRI and speech assessments, and testing in independent cohorts, are essential to establish their reliability and clinical relevance for monitoring brain network changes. Li, Qingyue; Alexopoulou, Zampeta-Sofia; Dyrba, Martin; Mallick, Elisa; Tröger, Johannes; Spruth, Eike; Altenstein, Slawek; Bartels, Claudia; Glanz, Wenzel; Incesoy, Enise I; Butryn, Michaela; Kilimann, Ingo; Sodenkamp, Sebastian; Maier, Franziska; Rostamzadeh, Ayda; Osterrath, Antje; Priller, Josef; Schneider, Anja; Wiltfang, Jens; Laske, Christoph; Falkenburger, Björn; Wagner, Michael; Duezel, Emrah; Spottke, Annika; Petzold, Gabor C; Jessen, Frank; König, Alexandra; Köhler, Stefanie; Teipel, Stefan; DELCODE, DESCRIBE study groups
New paper out: TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.: Feiten, Astrid Feentje; Dahm, Kilian; Schlepckow, Kai; et al.
Nature Communications Vol. 17, no. 1, p. 2002 http://dlvr.it/TRQqMH | Please share #dzne #papers
Nature Communications Vol. 17, no. 1, p. 2002 http://dlvr.it/TRQqMH | Please share #dzne #papers
TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism. - DZNEPUB
Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer's disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in major immunometabolic pathways, and enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis. In accordance, metabolic activity correlated with phagocytic capacity. Finally, we performed chronic treatment with a TREM2 agonist antibody and identified a window of TREM2 expression where microglia are most responsive, thereby informing clinical applications of TREM2 agonists. Feiten, Astrid Feentje; Dahm, Kilian; Schlepckow, Kai; van Lengerich, Bettina; Suh, Jung H; Reifschneider, Anika; Wefers, Benedikt; Bartos, Laura M; Wind, Karin; de Weerd, Lis; Ulas, Thomas; De-Domenico, Elena; Grundschöttel, Pia; Paulusch, Stefan; Tast, Benjamin; Honda, Tamisa; Müller, Stephan A; Becker, Matthias; Khalin, Igor; Ricci, Alessio; Liesz, Arthur; Brunner, Bettina; Krenner, Claudia; Buschmann, Katrin; Nuscher, Brigitte; Spieth, Lena; Junker, Niklas; Berghoff, Stefan A; Davis, Sonnet S; Neher, Jonas J; Wurst, Wolfgang; Plesnila, Nikolaus; Lewcock, Joseph W; Simons, Mikael; Lichtenthaler, Stefan F; Di Paolo, Gilbert; Brendel, Matthias; Capell, Anja; Monroe, Kathryn M; Schultze, Joachim L; Haass, Christian
New paper out: Alterations in cerebrospinal fluid levels of myelin- and oligodendrocyte-related proteins in sporadic Creutzfeldt–Jakob disease: Maass, Fabian; Thomas, Carolina; Kurvits, Lille; et al.
Acta Neuropathologica Communications Vol. 14, no. 1, p. 51 http://dlvr.it/TRQWv6 | Please share #dzne #papers
Acta Neuropathologica Communications Vol. 14, no. 1, p. 51 http://dlvr.it/TRQWv6 | Please share #dzne #papers
Alterations in cerebrospinal fluid levels of myelin- and oligodendrocyte-related proteins in sporadic Creutzfeldt–Jakob disease - DZNEPUB
Recent evidence suggests glial dysfunction, particularly involving oligodendrocytes and myelin, as an important part of the primary disease mechanism of sporadic Creutzfeldt–Jakob disease. To the best of our knowledge, cerebrospinal fluid (CSF) biomarkers reflecting oligodendrocyte or myelin damage have not yet been systematically investigated in this context. CSF samples from patients with sporadic Creutzfeldt–Jakob disease (CJD), Alzheimer's disease (AD) and non-neurodegenerative controls (n = 18, respectively) were included in the study, and levels of myelin basic protein (MBP), neural/glial antigen 2 (NG2) and cyclic nucleotide 3′-phosphodiesterase (CNPase) were quantified. Additionally, p25-positive cells were quantified in autopsy tissue from the frontal and parietal cortical regions of five patients with CJD and four controls. In the primary cohort, MBP quantification revealed significantly higher CSF levels in CJD compared to AD (p = 0.004) and controls (p = 0.0001) and this difference remained significant after adjustment for age and neurofilament light chain (NfL), indicating that MBP elevations cannot be explained solely by neuroaxonal degeneration. Significant differences were also found for CNPase in CJD compared to AD (p = 0.0011) and controls (p = 0.0004). There were no differences in NG2 levels (p > 0.05) among the groups. However, no significant differences were observed in the total number of p25-positive mature oligodendrocytes between CJD and controls in cortical brain tissue (p > 0.05). Additionally, MBP and NfL were quantified in a second cohort of 28 CJD and 20 biomarker-defined AD patients. In this cohort, characterized by more advanced AD pathology, MBP strongly covaried with NfL and no longer differed between diagnostic groups, suggesting a greater influence of neuroaxonal injury on MBP levels in advanced disease stages. In conclusion, in CJD, MBP elevations appear to be only partly related to neuroaxonal degeneration and may reflect disease-related myelin involvement.The online version contains supplementary material available at 10.1186/s40478-026-02247-5. Maass, Fabian; Thomas, Carolina; Kurvits, Lille; Hermann, Peter; Schmitz, Matthias; Bähr, Mathias; Stadelmann, Christine; Zechel, Sabrina; Canaslan, Sezgi; Zerr, Inga
New paper out: A physically and mentally active lifestyle relates to younger brain and cognitive age: Behrenbruch, Niklas; Schwarck, Svenja; Schumann-Werner, Beate; et al.
GeroScience http://dlvr.it/TRPxyw | Please share #dzne #papers
GeroScience http://dlvr.it/TRPxyw | Please share #dzne #papers
A physically and mentally active lifestyle relates to younger brain and cognitive age - DZNEPUB
Resistance to age-related pathological changes (brain maintenance), including Alzheimer’s disease, cerebrovascular disease, and neurodegeneration may promote cognitive resilience in aging. However, how lifestyle and health profiles relate to successful cognitive and brain aging remains poorly understood. In a novel, deeply phenotyped cohort of 211 cognitively unimpaired older adults (age = 71.0 ± 7.4 years, 46% female), we characterized principal components of lifestyle and health using questionnaire, fitness, and blood data. We estimated cognitive age gap (CAG) based on comprehensive neuropsychological data and brain age gap (BAG) based on brain-pathology markers, including plasma biomarkers of Alzheimer’s pathology (pTau217 and Aβ1-42/Aβ1-40), MRI-based measures of white matter hyperintensities, perivascular spaces, and brain atrophy. Regression analyses tested how the observed lifestyle-health profiles were related to CAG and BAG. Seven principal components explained 49% of the variance in health and lifestyle. The second component, characterized by a mentally and physically active life and low cardiovascular risk, was associated with lower CAG (β = − 0.66, p < 0.001) and BAG (β = − 0.52, p = 0.003), reflecting a younger-than-expected brain and cognitive age, respectively. The association of an active lifestyle and lower CAG was partially mediated by BAG. Higher CAG was also associated with other lifestyle components characterized by low mental stimulation. APOE-ε4 carriers exhibited higher BAG. In conclusion, a lifestyle combining low cardiovascular risk, high mental engagement throughout life and high physical activity/fitness is jointly associated with less-than-expected brain pathology and better-than-expected cognitive performance, supporting its involvement in brain maintenance and cognitive resilience to aging. Behrenbruch, Niklas; Schwarck, Svenja; Schumann-Werner, Beate; Molloy, Eóin N.; Garcia Garcia, Berta; Hochkeppler, Anne; Fischer, Larissa; Büchel, Anna-Therese; Incesoy, Enise I.; Bernal, Jose; Vockert, Niklas; Müller, Patrick; Behnisch, Gusalija; Morgado, Bárbara; Esselmann, Hermann; Seidenbecher, Constanze I.; Schott, Björn H.; Barthel, Henryk; Sabri, Osama; Wiltfang, Jens; Kreissl, Michael C.; Düzel, Emrah; Maass, Anne
New paper out: Proton channel Hv1 modulates microglial responses to neurological disorders: Stratmann, Maite; Gagliardi, Caterina; Capasso, Melania
Frontiers in biophysics Vol. 3, p. 1681011 http://dlvr.it/TRPhBV | Please share #dzne #papers
Frontiers in biophysics Vol. 3, p. 1681011 http://dlvr.it/TRPhBV | Please share #dzne #papers
Proton channel Hv1 modulates microglial responses to neurological disorders - DZNEPUB
Proton channels are transmembrane proteins that enable selective proton (H+) transport. The voltage-gated proton channel Hv1 or HVCN1 is the only one found in mammalian cells, primarily in immune cells, where it facilitates rapid proton extrusion in response to membrane depolarization, mediating outward proton currents. Therefore, it is well equipped to support NADPH-oxidase function, facilitating the proton flux that maintains physiological pH and membrane potential for efficient reactive oxygen species (ROS) production. In the central nervous system (CNS), Hv1 is predominantly found in microglia. Its role in microglia homeostasis is yet to be elucidated; however, recent research has highlighted its involvement in neurological conditions, including demyelinating disease, spinal cord injury, stroke, and Parkinsonism. These studies have shown beneficial effects of Hv1 deletion, including improved neurological function, reduced microglial activation, enhanced myelination, and decreased neuroinflammation. This review explores the role of Hv1 in the CNS and its potential as a therapeutic target in neurodegenerative diseases. Stratmann, Maite; Gagliardi, Caterina; Capasso, Melania
New paper out: Partizipation in der VersorgungsforschungParticipation in health services research: Hoffmann-Hoffrichter, Anna Louisa; Manietta, Christina; Rommerskirch-Manietta, Mike; et al.
Zeitschrift für Gerontologie und Geriatrie http://dlvr.it/TRPNlj | Please share #dzne #papers
Zeitschrift für Gerontologie und Geriatrie http://dlvr.it/TRPNlj | Please share #dzne #papers
Partizipation in der VersorgungsforschungParticipation in health services research - DZNEPUB
HintergrundModelle, die Menschen mit Demenz und Angehörige sowie Expert:innen aus verschiedenen Versorgungssettings in Forschung aktiv einbeziehen, sind bisher im deutschsprachigen Kontext nicht implementiert. Diese sind notwendig, um auch die Perspektive der „Mitforschenden“ aktiv einzubinden und Themen aufzugreifen, die sich am Alltag von Menschen mit Demenz und ihren Angehörigen und in der Versorgungspraxis Tätigen orientieren.Ziel der ArbeitDas Ziel ist die Entwicklung eines vorläufigen Frameworks für gemeinsames Forschen.Material und MethodenDas Vorgehen beinhaltet einen partizipativen Ansatz mit Stakeholdern verschiedener Personengruppen. Dazu zählen Menschen mit Demenz, Angehörige sowie Expert:innen aus dem langzeit- und akutstationären Setting. Es wurde ein Modell der partizipativen Forschung in die deutsche Sprache übersetzt und in virtuellen Meetings mit Stakeholdern besprochen, diskutiert und konsentiert. Die Ergebnisse wurden in einem Workshop besprochen, um die als notwendig erachtete Unterstützung der „Mitforschenden“ herauszuarbeiten. Die Treffen wurden in Protokollen festgehalten und inhaltsanalytisch deduktiv induktiv ausgewertet.ErgebnisseInsgesamt nahmen 13 Stakeholder an dem partizipativen Vorhaben teil. Das Framework für gemeinsames Forschen beinhaltet Grundprinzipien, Tätigkeiten und Unterstützungsbedarfe des gemeinsamen Forschens.DiskussionNeben Expert:innen aus unterschiedlichen Settings der Gesundheitsversorgung möchten und können auch Menschen mit Demenz und Angehörige aktiv in Forschung einbezogen werden. Um das vorläufige Framework weiterzuentwickeln, wird es in Projekten partizipativer Forschung am Deutschen Zentrum für Neurodegenerative Erkrankungen (DZNE) Standort Witten erprobt und verdichtet. Hoffmann-Hoffrichter, Anna Louisa; Manietta, Christina; Rommerskirch-Manietta, Mike; Roes, Martina
New paper out: Social networks of people with dementia: Roles of informal and formal contact persons: Hofbauer, Lena M.; Knecht, Hanna L.; Rodriguez, Francisca S.
Journal of public health http://dlvr.it/TRNpz2 | Please share #dzne #papers
Journal of public health http://dlvr.it/TRNpz2 | Please share #dzne #papers
Social networks of people with dementia: Roles of informal and formal contact persons - DZNEPUB
AimStudies on the social environment of people with dementia are largely limited to the closest informal contacts of people with dementia. The aim of this study was to gain a deeper understanding of the roles of both informal and formal contacts.Subject and methodsParticipants (n = 405) who replied to items concerning the social networks of people with dementia in the Social Resources in the Living Environment of People with Dementia (SoRe-Dem) Study were included. Participants were asked about the frequency of contact between contact persons and people with dementia, contact persons’ roles in the perceived progression of dementia, and contact persons’ influence on life with dementia. Participants also reported on conversation partners and characteristics of a good support network for people with dementia.ResultsFrequency of contact showed medium-to-high correlations with impact on perceived dementia progression and life with dementia. Partners and other close informal contacts consistently emerged as particularly important, including for conversations. A good support network was described as comprising both formal and informal contacts that take a person-centred approach, enable individualised activities, support the daily routine, aid integration into the community, educate about dementia, and provide emotional support.ConclusionOur findings underscore the critical importance of partners and other close informal contacts in all aspects of the daily lives of people with dementia. Strengthening the quality of contributions by the close network and increasing contact with the broader network could improve the lives of people with dementia. Hofbauer, Lena M.; Knecht, Hanna L.; Rodriguez, Francisca S.
New paper out: Clinical course and prognosis of chronic autoimmune neuropathies requiring intensive care: a retrospective cohort study.: Preßler, Hannah; Schwarz, Lisa; Streit, Simon; et al.
Journal of neurology Vol. 273, no. 2, p. 165 http://dlvr.it/TRNYDL | Please share #dzne #papers
Journal of neurology Vol. 273, no. 2, p. 165 http://dlvr.it/TRNYDL | Please share #dzne #papers
Clinical course and prognosis of chronic autoimmune neuropathies requiring intensive care: a retrospective cohort study. - DZNEPUB
Data on chronic autoimmune neuropathies (CAN) requiring intensive care unit (ICU) treatment are limited. This study investigated clinical and neuropathological features, immunotherapies, and outcomes of ICU-treated CAN patients.Retrospectively, we analyzed patients with CAN admitted to the ICU between 2007 and 2024. Outcomes, assessed by Inflammatory Neuropathy Cause and Treatment (INCAT) score and modified Rankin scale (mRS), were compared to age, sex, and diagnosis-matched non-ICU outpatients using ordinal and binary logistic regression.Among 21 included patients (chronic inflammatory demyelinating neuropathies (CIDP): n = 15, other CAN: n = 6), 95% required mechanical ventilation and exhibited severe tetraparesis at disease nadir. Biopsies from CIDP patients revealed moderate-to-severe chronic axonal loss with variable CD8 + T-cell infiltration (9/11), and complement deposition (C5b-9) was detected in all samples (n = 8/8). All patients received first-line immunotherapy at ICU, 62% required 'escalation' (rituximab: n = 13, cyclophosphamide: n = 3). Five (24%) remained refractory, receiving daratumumab (n = 3), efgartigimod (n = 1), or autologous stem cell transplantation (n = 1). Six patients (29%) died, whereas survivors showed marked improvement with median change of - 2 mRS points (95% CI - 5 to - 2) and - 6 INCAT points (95% CI - 8 to- 5) at last follow-up. However, ICU-treated patients had significantly higher odds of worse long-term outcomes than matched non-ICU patients (adjusted cumulative OR: mRS 7.1 95% CI 1.9-27.3, INCAT 6.4 95% CI 1.7-23.2).Severe CAN requiring ICU treatment is associated with high mortality, but meaningful recovery is possible in survivors. Neuropathology confirmed combined cellular and humoral mechanisms, supporting personalized, mechanism-guided therapeutic approaches. Preßler, Hannah; Schwarz, Lisa; Streit, Simon; Aigner, Annette; Schleicher, Alicia; Stascheit, Frauke; Arlt, Friederike A; Zinnow, Viktoria; Khorassani, Tatjana; Prüss, Harald; Böhmerle, Wolfgang; Meisel, Andreas; Stenzel, Werner; Scheibe, Franziska